It is well established that some organic compounds can crystallize in a number of different polymorphic forms or crystal habits, which may comprise the compound as such, solvates of the compound, hydrates of the compound, or combinations thereof. Alternatively, the compound, solvate or hydrate may exist as an amorphous solid.
When a compound containing crystal polymorphs is used as a nutraceutical, it is often necessary to produce a substance having a specific crystal form to guarantee the consistency of physicochemical and biological properties of the compound. Furthermore, in the process of manufacturing a drug substance, it is often important to separate out a particular form of crystal during the crystallization procedure, in order to maintain defined levels of the yield and purification efficiency.
Green tea, the beverage made from the unfermented leaves of Camellia sinensis, contains many constituents, including polyphenols which are commonly known as catechins or flavonoids. Catechins are thought to be responsible for many of the biological effects of tea. Epigallocatechin-3-gallate (EGCG) is the major catechin from green tea. EGCG is a compound of interest among the green-tea-derived catechins because it exhibits a strong antioxidant effect. Furthermore, EGCG has been associated with beneficial antioxidant, anti-inflammatory, and anti-carcinogenic effects. Yao et al. demonstrated that EGCG protects against oxidative stress-induced mitochondria-dependent apoptosis (2008); Potenza et al. found that EGCG improves endothelial function and insulin sensitivity, reduces blood pressure, and protects against myocardial ischemia-reperfusion injury in a mouse model of metabolic syndrome (2007); Katiyar et al. found that EGCG inhibits the effects of oxidative stress and prevents carcinogenesis (2001); Rezai-Zadeh et al. further studied EGCG's use in preventing and treating neurodegenerative diseases by showing that EGCG modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in a mouse model of Alzheimer's disease (2005); and Collins et al. demonstrated that EGCG suppresses hepatic gluconeogenesis by activating the 5′-AMP-activated protein kinase (AMPK) (2007). Elucidation of these molecular actions of EGCG substantiates the compound as a versatile modulator of cellular responses that may contribute to disease pathogenesis. Alzheimer's disease (AD) is a devastating neurodegenerative disease that currently affects an estimated 4.5 million Americans, costing the U.S. more than $100 billion annually. Finding a treatment that could delay onset by five years could reduce the number of individuals with AD by nearly 50 percent after 50 years. A promising approach to drug development for AD is to screen natural compounds, such as EGCG, which already have some available information regarding toxicity, metabolism, and possible therapeutic efficacy. In addition, EGCG and caffeine are effective in reducing beta-amyloid levels and plaque formation in transgenic mouse models of Alzheimer's disease.
Depending on the administration route desired in therapy utilizing EGCG, it may be desirable to improve or at least control the stability and water solubility of the EGCG to obtain a desired bioavailability profile. Furthermore, it can assist the manufacturing or purification process if the stability and water solubility of the EGCG can be controlled. In principle, the water solubility of polymorphic forms of an organic compound is not necessarily the same for all forms. Therefore, the use of specific crystalline forms or habits can offer useful control of the water solubility. Even a slight adjustment to the water-solubility by means of an adjustment to the polymorphic form can offer useful processing or biological advantages.